EP0161534A2 - Procédé pour la synthèse de pyridoimidazo rifamycines - Google Patents
Procédé pour la synthèse de pyridoimidazo rifamycines Download PDFInfo
- Publication number
- EP0161534A2 EP0161534A2 EP85104790A EP85104790A EP0161534A2 EP 0161534 A2 EP0161534 A2 EP 0161534A2 EP 85104790 A EP85104790 A EP 85104790A EP 85104790 A EP85104790 A EP 85104790A EP 0161534 A2 EP0161534 A2 EP 0161534A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- rifamycin
- formula
- methyl
- pyrido
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 22
- 230000015572 biosynthetic process Effects 0.000 title abstract 2
- 238000003786 synthesis reaction Methods 0.000 title abstract 2
- HJYYPODYNSCCOU-ODRIEIDWSA-N rifamycin SV Chemical compound OC1=C(C(O)=C2C)C3=C(O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O HJYYPODYNSCCOU-ODRIEIDWSA-N 0.000 claims abstract description 25
- -1 hydroxy-(C2-4)-alkyl Chemical group 0.000 claims abstract description 19
- 229930189077 Rifamycin Natural products 0.000 claims abstract description 13
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 229960003292 rifamycin Drugs 0.000 claims abstract description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 4
- 150000002367 halogens Chemical class 0.000 claims abstract description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 4
- 229940081192 rifamycins Drugs 0.000 claims abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims abstract 2
- 239000002904 solvent Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- RAFHKEAPVIWLJC-OQQFTUDCSA-N Rifamycin O Natural products COC1C=COC2(C)Oc3c(C)c(O)c4C(=O)C(=CC5(OCC(=O)O5)c4c3C2=O)NC(=O)C(=C/C=C/C(C)C(O)C(C)C(O)C(C)C(OC(=O)C)C1C)C RAFHKEAPVIWLJC-OQQFTUDCSA-N 0.000 claims description 11
- RAFHKEAPVIWLJC-TWYIRNIGSA-N z67lem9p1w Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)N2)C)OC)C(C(=C3O)C)=C1C1=C3C(=O)C2=C[C@]11OCC(=O)O1 RAFHKEAPVIWLJC-TWYIRNIGSA-N 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- 239000011630 iodine Substances 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 8
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000007795 chemical reaction product Substances 0.000 claims description 5
- 239000007800 oxidant agent Substances 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 150000002334 glycols Chemical class 0.000 claims description 3
- 150000008282 halocarbons Chemical class 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 125000005907 alkyl ester group Chemical group 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- BTVYFIMKUHNOBZ-QXMMDKDBSA-N rifamycin s Chemical class O=C1C(C(O)=C2C)=C3C(=O)C=C1NC(=O)\C(C)=C/C=C\C(C)C(O)C(C)C(O)C(C)C(OC(C)=O)C(C)C(OC)\C=C/OC1(C)OC2=C3C1=O BTVYFIMKUHNOBZ-QXMMDKDBSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims 1
- 150000003222 pyridines Chemical class 0.000 claims 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 150000001875 compounds Chemical class 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- HJYYPODYNSCCOU-ZDHWWVNNSA-N Rifamycin SV Natural products COC1C=COC2(C)Oc3c(C)c(O)c4c(O)c(NC(=O)C(=C/C=C/C(C)C(O)C(C)C(O)C(C)C(OC(=O)C)C1C)C)cc(O)c4c3C2=O HJYYPODYNSCCOU-ZDHWWVNNSA-N 0.000 description 14
- 229940109171 rifamycin sv Drugs 0.000 description 14
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- ORLGLBZRQYOWNA-UHFFFAOYSA-N 4-methylpyridin-2-amine Chemical compound CC1=CC=NC(N)=C1 ORLGLBZRQYOWNA-UHFFFAOYSA-N 0.000 description 9
- 229950011175 aminopicoline Drugs 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 5
- 235000010323 ascorbic acid Nutrition 0.000 description 5
- 229960005070 ascorbic acid Drugs 0.000 description 5
- 239000011668 ascorbic acid Substances 0.000 description 5
- 241000786363 Rhampholeon spectrum Species 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 150000003927 aminopyridines Chemical class 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- BTVYFIMKUHNOBZ-ZDHWWVNNSA-N Rifamycin S Natural products COC1C=COC2(C)Oc3c(C)c(O)c4C(=O)C(=CC(=O)c4c3C2=O)NC(=O)C(=C/C=C/C(C)C(O)C(C)C(O)C(C)C(OC(=O)C)C1C)C BTVYFIMKUHNOBZ-ZDHWWVNNSA-N 0.000 description 2
- BTVYFIMKUHNOBZ-ODRIEIDWSA-N Rifamycin S Chemical compound O=C1C(C(O)=C2C)=C3C(=O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O BTVYFIMKUHNOBZ-ODRIEIDWSA-N 0.000 description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000013065 commercial product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- NQIBQILAMKZKFE-UHFFFAOYSA-N 2-(5-bromo-2-fluorophenyl)-3-fluoropyridine Chemical compound FC1=CC=C(Br)C=C1C1=NC=CC=C1F NQIBQILAMKZKFE-UHFFFAOYSA-N 0.000 description 1
- WGOLHUGPTDEKCF-UHFFFAOYSA-N 5-bromopyridin-2-amine Chemical compound NC1=CC=C(Br)C=N1 WGOLHUGPTDEKCF-UHFFFAOYSA-N 0.000 description 1
- CMBSSVKZOPZBKW-UHFFFAOYSA-N 5-methylpyridin-2-amine Chemical compound CC1=CC=C(N)N=C1 CMBSSVKZOPZBKW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-DUZGATOHSA-N D-isoascorbic acid Chemical compound OC[C@@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-DUZGATOHSA-N 0.000 description 1
- 241000187654 Nocardia Species 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 210000001557 animal structure Anatomy 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229940120503 dihydroxyacetone Drugs 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 235000010350 erythorbic acid Nutrition 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 229940006461 iodide ion Drugs 0.000 description 1
- 229940026239 isoascorbic acid Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- OSILBMSORKFRTB-UHFFFAOYSA-N isoquinolin-1-amine Chemical compound C1=CC=C2C(N)=NC=CC2=C1 OSILBMSORKFRTB-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- SQTCRTQCPJICLD-KTQDUKAHSA-N rifamycin B Chemical compound OC1=C(C(O)=C2C)C3=C(OCC(O)=O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O SQTCRTQCPJICLD-KTQDUKAHSA-N 0.000 description 1
- SQTCRTQCPJICLD-OQQFTUDCSA-N rifomycin-B Natural products COC1C=COC2(C)Oc3c(C)c(O)c4c(O)c(NC(=O)C(=C/C=C/C(C)C(O)C(C)C(O)C(C)C(OC(=O)C)C1C)C)cc(OCC(=O)O)c4c3C2=O SQTCRTQCPJICLD-OQQFTUDCSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- R is hydrogen or acetyl and R and R2 independently represent hydrogen, (C 1-4 )-alkyl, benzyloxy, mono- or di-(C 1-3 )-alkylamino-(C 1-4 ) -alkyl, (C 1-3 ) -alkoxy-(C 1-4 )-alkyl, hydroxymethyl, hydroxy-(C 2-4 )-alkyl, nitro, or R 1 and R 2 taken together with two consecutive carbon atoms of the pyridine nucleus form a benzene ring optionally substituted by one or two methyl or ethyl groups are known in the patent literature; see, for instance, US patent No. 4341785 published on July 27, 1982.
- the known process was carried out by reacting a molar amount of a 3-halogen rifamycin S of formula wherein R represented hydrogen or acetyl and halo preferably represented bromine or iodine, with from about 2 to about 8 molar equivalents of an appropriate 2-amino-pyridine of formula III.
- a compound of formula was obtained, which was preferably isolated and characterized, and was subsequently treated with ascorbic acid in order to give the end compounds of formula I.
- the present invention refers to a new method for preparing pyrido-imidazo-rifamycins of general formula wherein R is hydrogen or acetyl, R and R 2 independently represent hydrogen, (C 1-4 )-alkyl, benzyloxy, mono- or di-(C 1-3 )--alkylamino-(C 1-4 )-alkyl, (C 1-3 )-alkoxy-(C 1-4 )-alkyl.
- (C 1-4 )-alkyl indicates straight or branched alkyl groups as, for instance, methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, isobutyl and tert.-butyl, while the term (C1-3)-alkoxy mainly designates the groups methoxy, ethoxy, propoxy or isopropoxy.
- the compounds of formula I are endowed with outstanding antibacterial properties both in vitro and in vivo. Because of their poor absorption by animal organs and tissues when administered by oral route, they have proved to be particularly useful in combatting the microbial infections of the gastro-intestinal tract.
- rifamycin 0, which is a commercial product is used as the starting rifamycin substrate Easily obtainable by chemical transformation of rifamycin B, as described in French Patent FM 739, or directly obtainable by fermentation of Nocardia strains (unexamined Japanese publication No. 15518/66) or by fermentation of Streptomyces strains (Belgian patent No. 751182) ].
- the rifamycin 0 is reacted under mild conditions with a selected 2-aminopyridine of formula III, in a suitable solvent or solvent system from which, by means of techniques known to a man* skilled in the art, the desired end products are recovered, wherein R 1 and R 2 have the above mentioned meanings and R is acetyl, with yields varying from about 60% to about 90% calculated on the starting rifamycin O.
- the compounds of formula I so obtained can subsequently be subjected to an alkaline hydrolysis to give the corresponding compounds of formula I wherein R is hydrogen.
- a molar amount of rifamycin 0 of formula II is reacted with from about 1 to about 9 molar equivalents of a 2-aminopyridine of formula III and, preferably, from about 2 to about 6 molar equivalents of said aminopyridine.
- the reaction is carried out in the presence of a solvent or of a solvent system, which is generally selected among those commonly used in rifamycins chemistry.
- a solvent or of a solvent system which is generally selected among those commonly used in rifamycins chemistry.
- aromatic hydrocarbons like benzene and toluene
- lower halogenated hydrocarbons like methylene chloride, chloroform, 1,2-dichloroethane and analogs
- lower alkanols like methanol, ethanol, propanol, isopropanol or n-butanol
- Lower alkyl esters of lower aliphatic acids, glycols, acetonitrile, dioxane and tetrahydrofuran can also conveniently be employed.
- solvents can be used alone, or in admixture among them, or also in admixture with water, in different volumetric ratios.
- the solvents which have given the best results are benzene, toluene, the lower halogenated hydrocarbons, the lower alkanols alone or in admixture with water, acetonitrile, glycols, dioxane and tetrahydrofuran.
- the reaction takes place at ambient pressure and within wide limits of temperature, for instance between the room temperature and the boiling temperature of the reaction mixture. Usually, an interval comprised between the room temperature and about 60°C gives absolutely satisfactory results.
- the reaction is completed in a period of time which essentially depends on the nature of the aminopyridine substrate of formula III and on the conditions in which the reaction is carried out. Generally, from about 10 to about 100 hours are required to obtain the end products of formula I with the desired yields.
- the reaction course can be favored if the reaction itself is carried out in presence of iodine or of an appropriate system iodide/oxidizing agent, wherein the iodide can be, for instance, the iodide of an alkali or an alkaline-earth metal and the hydroiodide of the same starting 2-amino-piridine and the oxidizing agent can be an agent capable of oxidizing, in the employed reaction conditions, the iodide ion, in order to release iodine in the reaction ambient.
- the iodide can be, for instance, the iodide of an alkali or an alkaline-earth metal and the hydroiodide of the same starting 2-amino-piridine
- the oxidizing agent can be an agent capable of oxidizing, in the employed reaction conditions, the iodide ion, in order to release iodine in the reaction ambient.
- the iodine, or the system iodide/oxidizing agent can be present in the reaction ambient respectively in amounts from about 0.1 to about 1 molar equivalent, or in an amount which releases from about 0.1 to about 1 molar equivalent of iodine, for each mole of starting rifamycin O.
- reaction solution must subsequently be treated with a suitable reducing agent, like, for instance, ascorbic acid, isoascorbic acid or dihydroxyacetone.
- a suitable reducing agent like, for instance, ascorbic acid, isoascorbic acid or dihydroxyacetone.
- the so obtained compounds of formula I in which R is the acetyl group are recovered from the reaction medium according to conventional techniques.
- the excess of unreacted aminopyridine of formula III is eliminated from the organic phase by means of an aqueous solution of a mineral acid.
- the organic phase is then separated and optionally dried on a suitable agent like, for instance, sodium sulfate, and the end product is obtained by evaporating the solvent.
- the desired compounds are obtained by crystallization from the reaction ambient at a temperature of about O° to 10°C when solvent systems containing water are used.
- the compounds of formula I can be purified, if necessary, by crystallization from suitable solvents or solvent systems.
- the I.R. spectra have been performed in KBr with a Perkin-Elmer 281-B spectrophotometer.
- the 1 H-NMR and 13 C-NMR spectra have been performed in deuterochloroform with a Varian XL 100 spectrophotometer by using tetramethylsilane as internal standard.
- the U.V. spectra have been performed in absolute methanol with a Perkin-Elmer 552 spectrophotometer.
- the so obtained compound has the same chemico-physical characteristics as that obtained in Example 1.
- the compound was prepared according to the procedure described in example 2, starting from 15.1 g (0.02 moles) of rifamycin O and 6.48 g (0.06 moles) of 2-amino-5-methyl-pyridine. Yield 12.6 g (80% of theoretical). M.p. 193°-198°C (decomposition).
- Example 7 The procedure of example 7 is repeated, keeping the reaction solution at room temperature for 20 hours and in presence of 11 g (0.043 moles) of iodine. After treatment with 130 ml of aqueous 20% solution of ascorbic acid, 160.4 g (77% of theoretical) of title compound were obtained, identical with that obtained in Example 1.
- Example 10 By employing the same molar ratio rifamycin 0/2-amino--4-methyl-pyridine as in Example 10, using 450 ml of a 10:13 (v/v) mixture of ethanol/water and working under the same reaction conditions of Example 9, 91 g of pure title product were obtained with a yield of 86.7% of theoretical.
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- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- General Health & Medical Sciences (AREA)
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Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT85104790T ATE46512T1 (de) | 1984-05-15 | 1985-04-19 | Verfahren zur synthese von pyridoimidazorifamycin. |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT03463/84A IT1199374B (it) | 1984-05-15 | 1984-05-15 | Processo per la preparazione di pirido-imidazo-rifamicine |
| IT346384 | 1984-05-15 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| EP0161534A2 true EP0161534A2 (fr) | 1985-11-21 |
| EP0161534A3 EP0161534A3 (en) | 1987-03-04 |
| EP0161534B1 EP0161534B1 (fr) | 1989-09-20 |
Family
ID=11107845
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP85104790A Expired EP0161534B1 (fr) | 1984-05-15 | 1985-04-19 | Procédé pour la synthèse de pyridoimidazo rifamycines |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US4557866A (fr) |
| EP (1) | EP0161534B1 (fr) |
| JP (1) | JPS60252483A (fr) |
| AR (1) | AR241913A1 (fr) |
| AT (1) | ATE46512T1 (fr) |
| AU (1) | AU568934B2 (fr) |
| CA (1) | CA1215708A (fr) |
| DE (1) | DE3573120D1 (fr) |
| DK (1) | DK162647C (fr) |
| ES (1) | ES8603489A1 (fr) |
| FI (1) | FI81101C (fr) |
| GR (1) | GR851144B (fr) |
| IE (1) | IE58392B1 (fr) |
| IT (1) | IT1199374B (fr) |
| NO (1) | NO164242C (fr) |
| PH (1) | PH22007A (fr) |
| PT (1) | PT80446B (fr) |
| ZA (1) | ZA852971B (fr) |
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| US4341785A (en) | 1980-05-22 | 1982-07-27 | Alfa Farmaceutici S.P.A. | Imidazo-rifamycin derivatives with antibacterial utility |
-
1984
- 1984-05-15 IT IT03463/84A patent/IT1199374B/it active
-
1985
- 1985-04-19 ZA ZA852971A patent/ZA852971B/xx unknown
- 1985-04-19 DE DE8585104790T patent/DE3573120D1/de not_active Expired
- 1985-04-19 EP EP85104790A patent/EP0161534B1/fr not_active Expired
- 1985-04-19 AT AT85104790T patent/ATE46512T1/de not_active IP Right Cessation
- 1985-04-25 PH PH32186A patent/PH22007A/en unknown
- 1985-04-26 US US06/727,521 patent/US4557866A/en not_active Expired - Lifetime
- 1985-04-29 CA CA000480321A patent/CA1215708A/fr not_active Expired
- 1985-05-13 GR GR851144A patent/GR851144B/el unknown
- 1985-05-13 PT PT80446A patent/PT80446B/pt unknown
- 1985-05-14 JP JP60102528A patent/JPS60252483A/ja active Granted
- 1985-05-14 ES ES543115A patent/ES8603489A1/es not_active Expired
- 1985-05-14 FI FI851907A patent/FI81101C/fi not_active IP Right Cessation
- 1985-05-14 DK DK214685A patent/DK162647C/da not_active IP Right Cessation
- 1985-05-14 IE IE119185A patent/IE58392B1/en not_active IP Right Cessation
- 1985-05-14 NO NO851921A patent/NO164242C/no not_active IP Right Cessation
- 1985-05-15 AU AU42515/85A patent/AU568934B2/en not_active Expired
- 1985-05-15 AR AR85300385A patent/AR241913A1/es active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US4341785A (en) | 1980-05-22 | 1982-07-27 | Alfa Farmaceutici S.P.A. | Imidazo-rifamycin derivatives with antibacterial utility |
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Also Published As
| Publication number | Publication date |
|---|---|
| ES543115A0 (es) | 1986-01-01 |
| IT1199374B (it) | 1988-12-30 |
| AU568934B2 (en) | 1988-01-14 |
| PT80446B (pt) | 1987-11-11 |
| NO164242B (no) | 1990-06-05 |
| GR851144B (fr) | 1985-11-25 |
| DK214685D0 (da) | 1985-05-14 |
| NO164242C (no) | 1990-09-12 |
| DE3573120D1 (en) | 1989-10-26 |
| PH22007A (en) | 1988-05-02 |
| EP0161534A3 (en) | 1987-03-04 |
| JPH0469634B2 (fr) | 1992-11-06 |
| IE58392B1 (en) | 1993-09-08 |
| AR241913A1 (es) | 1993-01-29 |
| NO851921L (no) | 1985-11-18 |
| AU4251585A (en) | 1985-11-21 |
| IE851191L (en) | 1985-11-15 |
| ATE46512T1 (de) | 1989-10-15 |
| DK162647C (da) | 1992-04-13 |
| PT80446A (en) | 1985-06-01 |
| EP0161534B1 (fr) | 1989-09-20 |
| FI81101B (fi) | 1990-05-31 |
| FI851907A0 (fi) | 1985-05-14 |
| DK162647B (da) | 1991-11-25 |
| FI81101C (fi) | 1990-09-10 |
| CA1215708A (fr) | 1986-12-23 |
| IT8403463A0 (it) | 1984-05-15 |
| FI851907L (fi) | 1985-11-16 |
| JPS60252483A (ja) | 1985-12-13 |
| DK214685A (da) | 1985-11-16 |
| ES8603489A1 (es) | 1986-01-01 |
| US4557866A (en) | 1985-12-10 |
| ZA852971B (en) | 1985-12-24 |
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